Recently we described a model of chronic relapsing experimental allergic encephalomyelitis (EAE) induced by myelin basic protein (MBP) or MBP derived peptides in SJL/J (H-2s), PL/J (H-2u) and (SJLxPL)F1 mice. Extension of these studies to C57B1/10Sn (B10) and B10 congenic mice demonstrated clear MHC lingage of disease susceptibility. Mapping studies with B10.A intra H-2 recombinant mice implicated the I-A subregion. H-2s and H-2u mice responded to different encephalitogenic determinats on the MBP mmolecule. Studies with (SJLxPL)F1 mice showed that the response to the two determinants was not expressed co-dominantly. Crosses of B10 (non-responder) with SJL/J or B10.A responder mice led to (B10xSJL)F1 responder and (B10xB10.A)F1 non-responder mice. These findings raise questions which include the basis for the different immunological specificities in H-2s and H-2u mice, the basis for dominance of reactivity to peptide 1-37 in (SJLxPL)F1 mice, and the reason for dominat unresponsiveness in (B10xB10.A)F1 mice. The proposed research will investigate ways in which Ia antigens in homozygous and heterozygous animals affect the immune response against chemically defined epitopes of MBP. The results of these studies may provide an important insight into the relationship of HLA-DR antigens and autoimmunity in man as well as the basic mechanisms of the immune response to an autoantigen.